Faculty Bibliography

INTRODUCTION/BACKGROUND:Multiple endocrine neoplasia type 1 (MEN1) is the most common genetic syndrome causing neuroendocrine tumours (NET) with metastatic duodenopancreatic NET (dpNET) forming the predominant cause of MEN1-related mortality. Peptide receptor radionuclide therapy with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-Dotatate) is an established treatment for advanced dpNET. As MEN1 loss-of-function has been associated with potential radiosensitising effects, this retrospective study evaluated outcomes of patients with germline MEN1-associated NET after treatment with 177Lu-Dotatate. METHODS:This is a retrospective cohort study in patients with MEN1 and metastatic NET treated with 177Lu-Dotatate compared to a control group of patients with advanced sporadic pancreas NET (panNET). Survival outcomes, response rates and adverse events after the initiation of 177Lu-Dotatate were evaluated. RESULTS:A total of nineteen MEN1 patients with dpNET and fifty-seven sporadic panNET controls were included. No significant difference in median progression-free survival with 39.6 months (95%CI 13.7-65.5) in the MEN1 group versus 45.0 months (95%CI 35.7-54.3) in the control group was seen, with a hazard ratio of 1.086 (95%CI 0.60-1.98). Overall survival was similar between groups with 97.8 months (95%CI 36.3-159.3) and 89.3 months (95%CI 54.6-123.9), respectively, and a hazard ratio of 0.883 (95%CI 0.43-1.82). There were no significant differences in objective radiological response (44.4% in the MEN1 group versus 35.2% in the control group) or in grade ≥ 3 toxicity. CONCLUSION/CONCLUSIONS:MEN1 patients with advanced dpNET benefit equally from 177Lu-Dotatate treatment as those with sporadic panNET in terms of survival and response. These findings support the use of PRRT in MEN1-associated dpNET similar to sporadic cases.

Glucagonomas are a rare hormone-producing pancreatic neuroendocrine tumor (panNET), with an estimated incidence of 1 to 2 cases per million persons. They typically present at diagnosis as large, metastatic panNET and are characterized clinically by diabetes mellitus, weight loss, thromboembolic complications and necrolytic migratory erythema. The diagnosis of glucagonoma syndrome requires the presence of both elevated fasting plasma glucagon levels and glucagonoma symptoms. Staging relies on cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI), complemented by somatostatin receptor positron emission tomography (PET) imaging. Initial management of glucagonoma includes supportive therapy with supplementation of amino acids, essential fatty acids, zinc, and other micronutrients as well as glycemic control and anticoagulation. Surgical resection is the only curative treatment. For unresectable or metastatic disease, palliative management parallels that of nonfunctioning panNET and includes somatostatin analogues, targeted therapies, peptide receptor radionuclide therapy with radiolabeled somatostatin analogues, and cytotoxic chemotherapy. Prognosis depends on tumor stage and grade, with reported 10-year survival rates approaching 100% for localized disease and approximately 50% for metastatic glucagonoma. A rare hereditary cause of hyperglucagonemia due to glucagon receptor mutations is glucagon cell hyperplasia and neoplasia, also termed Mahvash disease. These patients develop alpha cell hyperplasia and panNET but lack the classical glucagonoma symptoms. In conclusion, fasting glucagon levels should be measured in patients with typical features such as necrolytic migratory erythema, an advanced panNET associated with cachexia and new-onset or worsening diabetes mellitus or diffuse alpha cell hyperplasia.

OBJECTIVE:Mitotane is e first-line medical treatment for adrenocortical carcinoma (ACC). Mitotane has substantial dr awbacks, including severe toxicity and contralateral gland destruction, whilst effective in only 25-30% of ACCs. To improve patient selection for mitotane therapy, this study aimed to identify tissue biomarkers associated with in vitro mitotane response. DESIGN/METHODS:Retrospective cohort study. METHODS:We performed transcriptomic and proteomic analyses on fresh-frozen human ACC tissues classified as responders (n=13), partial responders (n=10), or non-responders (n=7) based on in vitro mitotane-induced inhibition of cell proliferation. RESULTS:Responders showed distinct transcriptomic and proteomic signatures compared with partial and non-responders, whereas fewer differences were found between the latter groups. Integrating transcriptomic and clinicopathological data indicated that responders frequently had cortisol-producing ACC with metastases or nodal involvement. Furthermore, their transcriptomes aligned with aggressive, proliferative ACC subtypes described previously. Differential expression analysis identified 718 genes and 60 proteins that distinguished responders from non-responders. Pathway and network analyses revealed upregulation of cell cycle and collagen related genes and downregulation of mitochondria related genes and proteins in responders. CONCLUSIONS:In summary, transcriptomic and proteomic profiling offers promise to predict mitotane response in ACC. Our findings suggest that responders exhibit features of aggressive ACC, with distinct molecular characteristics that could serve as biomarkers for treatment selection.

PURPOSE/OBJECTIVE:To assess the results of patient-reported outcome measures (PROMs) in a national cohort of females with a prolactinoma by disease activity. METHODS:Females with prolactinoma included in the PRolaCT or ProlaC study were assessed cross-sectionally, comparing patients with active (prolactin above upper limit of normal (ULN)) and controlled (prolactin<ULN) disease. Disease and treatment characteristics were reported. Patients completed PROMs on symptoms (modified PRO-CTCAE), health-related quality of life (HR-QoL) (SF-36), anxiety and depressive symptoms (Hospital Anxiety and Depression Scale (HADS)), and disease burden (Leiden Bother and Needs Questionnaire for patients with Pituitary disease (LBNQ-Pituitary)). RESULTS:Four hundred and fifty females with a prolactinoma were included (active: n=223, controlled: n=227), most were treated with dopamine agonists (DAs) (97.0%). Fatigue was the most prevalent symptom in both patients with active and controlled disease (92.6%, and 86.4%, respectively) followed by concentration problems (79.0%, and 64.5%, respectively) (modified PRO-CTCAE, LBNQ-Pituitary). Anxiety and depressive symptoms were worse in patients with active compared to controlled disease (HADS-Anxiety: 8.0 ± 4.5 vs 6.4 ± 4.5 p<0.001. HADS-Depression: 6.4 ± 5.0 vs 4.7 ± 4.4 p<0.001). Disease burden was higher in patients with active compared to controlled disease (LBNQ-Pituitary: Total Bother 24.4 ± 22.9 vs 16.4 ± 17.9 (p<0.001). CONCLUSIONS:Females with a prolactinoma were most affected by fatigue and cognitive complaints. Although patients with active disease perceived more burden than patients with controlled disease, symptoms including fatigue, psychological and cognitive complaints were prevalent despite disease control. Therefore, improvement of treatment and rehabilitation strategies is needed.

CONTEXT/BACKGROUND:Temozolomide (TMZ) can be an effective medical treatment for aggressive pituitary tumors. In case of disease recurrence following TMZ treatment, however, treatment with the drug generally does not control tumor regrowth. OBJECTIVE:This work aimed to better understand the mechanisms of resistance of corticotroph tumors to TMZ in the context of heterogeneity of methylguanine-DNA methyltransferase (MGMT) expression. METHODS:We performed immunohistochemical analysis of the MGMT expression pattern in 25 corticotroph tumors to evaluate intratumoral heterogeneity. In addition, we created in vitro models of AtT20 corticotroph tumor cells with acquired TMZ-resistance after exposure to high- and low-dose TMZ, the latter representing a clinically achievable TMZ level. RESULTS:MGMT immunostaining in corticotroph tumors showed a considerable heterogeneous intertumoral and intratumoral distribution pattern in 80% of tumors. In the in vitro model, high- and low-dose TMZ challenges induced a 6.3- and 3.4-fold decreased sensitivity to the growth inhibitory effect of TMZ. TMZ-induced changes in cell cycle phases were lower in TMZ-resistant cells than in vehicle-challenged cells. TMZ-resistant cells had higher Mgmt messenger RNA and protein expression and 1.8-fold higher number of Mgmt-positive cells. No difference was observed in the level of Mgmt promoter methylation. CONCLUSION/CONCLUSIONS:Corticotroph pituitary tumors demonstrate a high intertumoral and intratumoral heterogeneity in MGMT expression. In an acquired TMZ-resistant corticotroph pituitary tumor cell model, TMZ resistance was associated with strong increase in MGMT expression and percentage of MGMT-positive cells. We hypothesize that clonal selection of high MGMT-expressing cells is involved in this acquired TMZ resistance.

Mesenteric fibrosis (MF) is an extensive fibrotic reaction common in small intestine neuroendocrine tumours (SI-NETs), which develops around mesenteric metastasis. While primary SI-NETs can remain asymptomatic for years, mesenteric metastasis (MM) and the resulting MF frequently leads to serious complications. Despite its clear impact on quality of life, MF pathophysiology remains poorly understood and treatment options are currently limited to surgical interventions. This review summarizes the literature on MF in SI-NET patients, emphasizing gaps in knowledge and potential research directions. Clinical research confirms that MF is a frequent complication, often causing severe morbidity, including mesenteric ischaemia and obstruction. Addressing these issues requires further research into MF pathogenesis and contributory factors, such as Elastic Vascular Sclerosis (EVS), which are currently underexplored. Advancing this field will necessitate collaboration, supported by clear definitions and standardized diagnostic and grading systems for MF linked to clinical data, which are presently lacking. While MF-directed translational research remains scarce, recent studies focusing on tumour microenvironment have begun to uncover possible pathways involved in MF. Serotonin, pro-fibrotic growth factors and cytokines may play a role in activating cancer-associated fibroblasts and immune cells within the tumour microenvironment, aggravating extracellular matrix protein deposition and possibly creating positive feedback loops which promote fibrosis. Recently classified as an organ, the mesentery may harbour unique properties for stimulating the establishment of MF. Emerging research is paving the way for new MF treatment options which are urgently needed.

OBJECTIVE:Cortisol excess in Cushing's disease (CD) induces widespread plasma protein alterations, affecting various pathways including coagulation and lipid metabolism. The extent to which these abnormalities normalize during long-term remission remains unclear. DESIGN/METHODS:Cohort study investigating plasma protein profiles in CD patients before, and during long-term remission. METHODS:EDTA plasma samples of 26 CD patients were collected during active disease and during long-term remission (median 4.4 years, interquartile range 3.3-5.1). Plasma protein profiles were generated using quantitative protein mass spectrometry for 159 proteins, including 21 coagulation-related proteins, 18 complement proteins, 15 transport proteins, and 14 apolipoproteins. Protein levels before and after remission were compared with 80 controls (false discovery rate-adjusted t-test) with similar age and sex distribution. RESULTS:During active CD, 78 out of 159 proteins differed from controls, including 11 coagulation proteins, 10 transport proteins, and 3 apolipoproteins. Gelsolin and extracellular matrix protein-1 were most significantly changed. Following remission, 69 proteins changed significantly relative to active disease, but normalization was incomplete. Of the 78 proteins initially altered, 56 were similar to controls upon remission. After remission, 31 proteins remained different from controls, including coagulation proteins factor IX and factor XIII A chain, apolipoprotein A-II, several complement factors and extracellular matrix protein-1. CONCLUSION/CONCLUSIONS:Active CD is associated with profound alterations in plasma protein profiles across various functional domains. Long-term remission is accompanied by substantial, but incomplete normalization of plasma proteins. Sustained plasma protein abnormalities may contribute to persistent morbidities and ongoing adverse health risks after remission of CD.

BACKGROUND:Relacorilant is a selective glucocorticoid receptor modulator designed to reduce excess cortisol activity by competing with cortisol for glucocorticoid receptor binding, mitigating the clinical manifestations of endogenous hypercortisolism (Cushing's syndrome). The aim of this study was to assess the efficacy and safety of relacorilant in adults with endogenous hypercortisolism. METHODS:This multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study enrolled adults with endogenous hypercortisolism and hypertension, hyperglycaemia, or both and was conducted at 77 study centres across 11 countries. Key inclusion criteria included being aged 18-80 years with at least two clinical signs or symptoms of hypercortisolism. In the open-label phase, patients received oral, once-daily relacorilant (escalation from 100 mg up to 400 mg) for 22 weeks. Patients who met response criteria were randomly assigned (1:1) by the interactive web response system to continue relacorilant 400 mg (or highest tolerated dose) or placebo for 12 weeks in the randomised-withdrawal phase. Participants and investigators were masked to treatment assignment. The primary outcome was the proportion of patients who lost hypertension response during the randomised-withdrawal phase compared between relacorilant and placebo at week 12. As per protocol, this outcome was assessed in all participants who received at least one dose of study drug in the study period (intention-to-treat population). Missing randomised-withdrawal week 12 values were considered a loss of response. Safety was assessed in all enrolled patients who received at least one dose of study drug in that period. This study is registered with ClinicalTrials.gov, NCT03697109. FINDINGS/RESULTS:Between Oct 16, 2018, and April 15, 2024, 404 patients were screened, 152 were enrolled, and 95 completed the open-label relacorilant phase. 62 patients met response criteria and were randomly assigned to relacorilant (30 total participants [21 met hypertension response criteria]) or placebo (32 total participants [22 met hypertension response criteria]). In the 30 participants in the relacorilant group, the mean age was 46·6 years (SD 11·0), 22 (73%) were female, and eight (27%) were male. In the 32 participants in the placebo group, the mean age was 48·8 years (SD 14·4), 26 (81%) were female, and six (19%) were male. During the randomised-withdrawal phase, significantly more patients with baseline hypertension who were randomly assigned to placebo lost hypertension control compared with those who continued relacorilant (proportion difference 34%; odds ratio 0·17 [95% CI 0·04-0·77]; p=0·022). In the randomised-withdrawal phase safety population, the most common adverse events in the 30 participants given relacorilant and the 32 participants given placebo were back pain (5 [17%] vs 6 [19%]), acne (3 [10%] vs 0), arthralgia (3 [10%] vs 3 [9%]), bursitis (3 [10%] vs 0), headache (3 [10%] vs 4 [13%]), and insomnia (0 vs 4 [13%]). There were no cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, vaginal bleeding associated with endometrial hypertrophy, drug-induced hypokalaemia, or drug-induced QT interval prolongation. INTERPRETATION/CONCLUSIONS:Patients treated with relacorilant were more likely to maintain hypertension control compared with patients treated with placebo. The findings support consideration of relacorilant as a therapeutic option to reduce the harmful and debilitating effects of endogenous hypercortisolism. FUNDING/BACKGROUND:Corcept Therapeutics.

PURPOSE/OBJECTIVE:We aimed to determine time trends in incidence, treatment and survival of patients with adrenocortical carcinoma in the Netherlands. METHODS:All 685 adult patients with adrenocortical carcinoma diagnosed between 1993 and 2020 in the Netherlands were included, using the nation-wide prospective Netherlands Cancer Registry. RESULTS:The median age-adjusted incidence rate based on the European Standard Population was 1.62 per million person-years [0.83-2.11] and was stable over time. We saw a gradual increase in stage III on diagnosis (13 to 25%) with a stable proportion of stage IV (40%). The five-year survival remained stable over time for stage I-II at 65% and stage III at 35%, while the survival for stage IV increased from 3% in 1993-1996 to 11% in 2017-2020. Since the Dutch Adrenal Network was founded in 2004, more patients were referred to an expert center (p<0.001), which was associated with increased survival (adjusted HR 0.70, 95%CI[0.57-0.85]). Multivariate cox-regression showed increased survival in all stages when treated with adrenalectomy (adjusted HR 0.53, 95%CI[0.43-0.65]) and mitotane therapy (adjusted HR 0.73, 95%CI[0.55-0.98]). In stage IV disease, adrenalectomy, surgical control of disease, chemotherapy and mitotane therapy were associated with increased survival. However, only 58% of mitotane users reached a therapeutic drug level and 59.5% discontinued treatment prematurely. CONCLUSIONS:The incidence of adrenocortical carcinoma is stable over time. The five-year survival for stage I-III remained stable, while the survival for stage IV increased. Factors associated with increased survival are centralization of care, adrenalectomy, surgical control of disease, chemotherapy and mitotane therapy.

BACKGROUND:Treatment for patients with bilateral adrenal tumours and cortisol excess is not standardised and poses a therapeutic dilemma. Untreated cortisol excess is associated with cardiometabolic morbidity and mortality, but bilateral adrenalectomy causes adrenal insufficiency and possibly life-threatening adrenal crises. Data on cardiovascular outcomes by treatment modality are scarce. In this study we aimed to evaluate mid-term and long-term clinical and biochemical outcomes in patients with bilateral adrenal tumours and cortisol excess by treatment strategy and diagnosis. METHODS:This retrospective, international cohort study (in 30 centres across 10 countries in Europe plus Singapore and the USA) included patients with bilateral adrenal tumours of 10 mm or larger, post-dexamethasone serum cortisol concentration of 50 nmol/L or higher, and at least 36 months of follow-up, with data collection beween Feb 2, 2024, and Jan 31, 2025. Patients were excluded if they had adrenocorticotropin hormone (ACTH)-dependent cortisol excess, ACTH-dependent nodular adrenal hyperplasia, partial glucocorticoid resistance syndrome, a diagnosis inconsistent with benign adrenocortical lesions, or received systemic oral or intravenous glucocorticoids other than replacement therapy following adrenalectomy. Primary endpoints were all-cause mortality and clinical and biochemical remission rates. Secondary endpoints were the incidence of cardiovascular events, prevalence of vascular and metabolic comorbidities, and incidence of adrenal crises. FINDINGS/RESULTS:Of 629 patients who were diagnosed between Jan 1, 2000, and Jan 31, 2022, 105 (17%) had Cushing's syndrome and 524 (83%) had mild autonomous cortisol secretion (MACS), median age was 62 years (IQR 54·0-68·0), and 426 (68%) were female. 85 (81%) of 105 patients with Cushing's syndrome underwent surgery, and 384 (73%) of 524 patients with MACS received non-specific symptomatic treatment (ie, never underwent adrenalectomy or received steroidogenesis inhibitors). Over a median follow-up of 6·8 years, biochemical remission was achieved in 46 (45%) of 102 patients with Cushing's syndrome and in 67 (13%) of 517 patients with MACS. In both groups, 7% of patients died (Cushing's syndrome: seven of 105; MACS: 38 of 524) and 12% (13 of 105) of patients with Cushing's syndrome and 16% (82 of 524) of those with MACS had at least one cardiovascular event, without substantial differences across treatments. Smoking emerged as key modifiable mortality and cardiovascular risk factor in all patients, and in patients with MACS who only received non-specific symptomatic therapy, post-dexamethasone cortisol was also associated with increased mortality. Bilateral adrenalectomy led to full biochemical remission, few non-fatal adrenal crises, and improved arterial hypertension. Unilateral adrenalectomy and steroidogenesis inhibitors yielded heterogeneous biochemical outcomes and no substantial comorbidity improvement. Non-specific symptomatic treatment in MACS was associated with worsening of all investigated comorbidities. INTERPRETATION/CONCLUSIONS:Although mortality and cardiovascular event rates were similar across treatments, surgery led to better biochemical control and more favourable comorbidity outcomes. FUNDING/BACKGROUND:None.